1-(2&#39;,3&#39;,4&#39;-trisubstituted-phenyl)-2-amino-alkanols-(1)and salts thereof

ABSTRACT

THE COMPOUNDS ARE 1-(2&#39;&#39;,3&#39;&#39;,4&#39;&#39;-TRISUBSTITUTED-PHENYL)-2AMINO-ALKANOLS-(1) AND ACID ADDITION SALTS THEREOF, USEFUL AS SYMPATHOMIMETICS IN WARM-BLOODED ANIMALS.

United States Patent ABSTRACT OF THE DISCLOSURE The compounds are1-(2',3',4'-trisubstituted-phenyl)-2- amino-alkanols-(l) and acidaddition salts thereof, useful as sympathomimetics in warm-bloodedanimals.

This is a continuation-in-part of copending application Ser. No.713,265, filed Oct. 16, 1967, now US. Pat. 3,657,244, issued Apr. 18,1972.

This invention relates to novel1-(2',3',4'-trisubstitutedpheny1)-2-secondary amino-alkanols-(l) andacid addition salts thereof, as well as to various methods of preparingthese compounds.

More particularly, the present invention relates to racemic mixtures ofa novel class of compounds of the wherein R is straight or branchedalkoxy of 1 to carbon atoms,

R: is hydrogen or lower alkyl, and

R is straight or branched alkyl of 4 to 8 carbon atoms,

cycloalkyl of 3 to 7 carbon atoms, or

Rs Q I where Z is straight or branched alkylene of 2 to 6 carbon atoms,

R, is hydrogen or methyl, and R is hydroxyl or methoxy;

their stereoisomeric components; their diastereomeric antipodes; andnon-toxic, pharm-acologically. acceptable acid addition salts of saidracemic mixtures, stereoisomers or diastereomeric antipodes.

The compounds according to the present invention may be prepared by anumber of dilferent methods involving well-known chemical principles,among which the following have proved to be particularly convenient andefiicient.

METHOD A By reducing a ketone of the formula 3,804,834 Patented Apr. 16,1974 wherein R R and R have the same meanings as in Formula I; each Reither is a hydrogen atom or is a protective group which if necessary issubsequently split olf, preferably by hydrolysis or hydrogenation, suchas acyl or benzyl; or both R, together with each other and the oxygenatoms to which they are attached, form an acetal group whose hydrocarbonmoiety preferably contains the diphenylmethylene or cyclohexylidenegroup; and R" is hydrogen or a protective group, such as benzyl.

The reduction may be carried out with the aid of hydrogen in thepresence of a hydrogenation catalyst; such as Raney nickel, platinum orpalladium; or also with the aid of complex hydrides, especially sodiumborohydride or lithium aluminum hydride; or also by means of theMeerwein-Ponndorf-Verley reduction.

The various protective groups may be split oif all at once or instepwise fashion, during or after the reduction, by conventionalmethods.

A starting compound of the Formula II may be obtained by customarymethods, such as by reacting a compound of the formula wherein R and Rhave the same meanings as in Formula I, R' has the same meaning as inFormula II, and X is chlorine, bromine or iodine, with an amine of theformula LHNR"R (IV) wherein R has the same meaning as in Formula I andR" has the same meaning as in Formula H.

, METHOD B By reducing a compound of the formula (III) ence of ahydrogenation catalyst, such as Raney nickel or palladium, or with acomplex hydride, such as lithium aluminium hydride or sodiumborohydride. If the reduction is carried out with the aid of a complexhydride, it is preferred if each R' in the starting compound of theFormula V is a protective group, especially benzyl, and these protectivegroups may be removed in customary fashion subsequent to the reductionreaction. If desired, in those cases where R,; is CH(OH), the Schiitsbase formed by the condensation reaction between Compound V and amine VImay also be used as the starting compound.

A dicarbonyl compound of the Formula V may be obtained by customarymethods, such as by oxidation of an analogously substituted aceto-,propio-, butyroor valerophenone with selenium oxide.

METHOD C By reacting a compound of the formula R O R1 (VIIa) H (VIIb)wherein R and R have the same meanings as in Formula I, R has the samemeanings as in Formula II, and X is chlorine, bromine or iodine, or amixture of Compounds VHa and VIIb, with an amine of the Formula IV. If Rand R" in the reaction product thus obtained are protective groups,these may subsequently be removed in conventional fashion.

A compound of the Formula VIIa or VIIb may be obtained by known methods,for instance by reducing a halo-ketone of the formula X (VIII) wherein RR R and X have the meanings defined above, with sodium borohydride.

METHOD D By reacting an amine of the formula I R: R O CH- flH-NH:

(in (1 wherein R R and R have the same meanings as in Formula VIIa,under reducing conditions, with a compound of the formula B7 on whereinR is hydrogen or straight-chain lower alkyl; R is straight or branchedlower alkyl, the sum of the carbon atoms in R and R being no greaterthan 7; and

R may further be Ra (X wherein Z is lower alkylene, the sum of thecarbon atoms in Z and R being no more than 5, and R and R have the samemeanings as in Formula Ia; and R and R together with each other, mayalso be alkylene of no more than 6 carbon atoms.

The reducing agent may be hydrogen in the presence of a hydrogenationcatalyst, such platinum. If R in Formula IX is a protective group whichmay be split off by hydrogenation, these protective groups maysimultaneously be split ofi. If R is acyl, these are removed subsequentto the reduction in customary fashion.

A complex hydride, such as sodium borohydride or lithium aluminiumhydride, may also be used as the reducing agent. Under those conditions,it is preferred to use as the starting material a compound of theFormula IX wherein R is a protective group, especially benzyl ordiphenylmethyl, and any protective groups present in the reactionproduct may subsequently be split off in customary fashion.

An amine of the Formula IX may be obtained by wellknown methods from ananalogously substituted isonitrosoketone, cyanhydrin, benzoylcyanide,hydrazine, hydrazide, azidophenone or diazophenone. However, it is notnecessary to prepare and isolate the amine IX separately; instead, ananalogously substituted starting compound mentioned in the precedingsentence may be subjected, as such, to the reductive substitutionreaction, whereby the amine IX is formed in situ and undergoes reactionwith Compound X.

4 METHOD E For the preparation of a compound of the Formula I wherein Ris hydrogen, by reducing a compound of the formula reduction.

METHOD F By reacting a compound of the formula wherein R and R have thesame meanings as in Formula I and R and R have the same meanings as inFormula II, with a compound of the formula R,-Y x111 wherein R has thesame meanings as in Formula I and Y is chlorine, bromine, iodine,arylsulfonyl or alkylsulfonyl. The reaction is advantageously carriedout in the presence of an acid-binding condensation agent, such assodium carbonate or potassium carbonate; however, the amine XII mayitself also serve as the acid-binding agent, provided it is present insufficient excess over and above the stoichiometrically required amount.The protective groups may subsequently be removed in customary fash-1011.

The compounds of the Formula I are organic bases and therefore form acidaddition salts with inorganic or organic acids. Examples of non-toxic,pharmacologically acceptable acid addition salts are those formed withhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,tartaric acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid,cyclohexylsulfuric acid, 8-chlorotheophylline or the like.

In those instances where methods A through F yield initially an acidaddition salt of a compound of the Formula I, this salt may be convertedinto the free base or into another acid addition salt by conventionalmethods, if desired.

If a starting compound for any of the methods described above exists instereoisomeric forms, a pure stereoisomer thereof may be used as thestarting compound.

If an end product of the Formula I contains only one asymmetric carbonatom, a racemic mixture thereof may, if desired, be separated into itsoptical antipode components by conventional methods. If more than onecenter of asymmetry are present, the racemates of the diastereomericpairs of antipodes may be separated from each other, and each pair mayin turn be separated into the individual antipodes. For the separationof the mirrorimage-isomers it is preferred to use fractional crystallization of their addition salts formed with optically active acids, such asdibenzoylor ditoluyl-a-tartaric acid.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. Itshould be understood, however, that the instant invention is not limitedsolely to the following particular examples.

EXAMPLE 1 270 gm. of 2,3,4-trihydroxy-acetophenone [prepared accordingto Badhwar, Org. Synthesis, 14, 14 (1934)] were admixed with 772 cc. ofacetone, 131 cc. of pyridine and 388 gm. of diphenyl-dichloro-methane,and the mixture was allowed to stand overnight. Thereafter, a solutionof 200 gm. of sodium hydroxide in 500 cc. of water was added thereto insmall portions, whereby the temperature of the reaction mixture rose tobetween 50 and 60 C. After about two hours of standing the reactionmixture was acidified with concentrated hydrochloride acid, theresulting stifl crystalline slurry was diluted with water, the crystalswere separated by vacuum filtration and washed with water, the filtercake was suspended in methanol, the slurry was vacuum filtered, and thefilter cake was washed with methanol, yielding2-hydroxy-3,4-diphenylmethylenedioxyacetophenone, M.P. 155l56 C.

249 gm. of 2 hydroxy 3,4 diphenyhnethylenedioxyacetophenone were admixedwith 1250 cc. of methanol and 288 cc. of dimethylsulfate, the mixturewas heated to 40 C., and then a solution of 204 gm. of potassiumhydroxide in 813 cc. of methanol was slowly added while stirring,whereby the temperature of the reaction mixture rose to 53 C. Themixture was stirred for 45 minutes more, was then cooled to roomtemperature, the precipitate formed thereby was separated by vacuumfiltration, and the filter cake was taken up in ether by stirring. Theinsoluble potassium bisulfate was separated by vacuum filtration, thefiltrate was filtered through charcoal, and the ether was distilled off.The residue was poured on a plate, whereby 2 methoxy3,4-diphenylmethylenedioxyacetophenone crystallized out. 39 gm. of thiscompound were dissolved in 346 cc. of benzene, cc. of bromine were addedto the solution dropwise, and the bromination was allowed toproceed at80 C. After the bromination had gone to completion the benzene wasdistilled ofl, the residue was crystallized fromisopropanol, thecrystalline product was collected by vacuum filtration, and the filtercake was washed with petroleum ether, yielding abromo 2 methoxy3,4-diphenylmethylenedioxy-acetophenone, M.P. 137 C.

63.8 gm. of this bromoketone were admixed with 52.5 gm. ofN-benzyl-cyclopentylamine and 250 cc. of benzene, the mixture wasrefluxed for two hours, ether was then added to the reaction solution,and the precipitated N- benzyl-cyclopentylamine hydrobromide wasseparated by vacuum filtration. The filtrate was evaporated in vacuo,the residue was dissolved in methanol, the solution was neutralized withdilute hydrochloric acid, and an equal amount of water was added. Theaqueous solution was then hydrogenated at 60 C. and 5 atmospheres untilthe theoretical amount of hydrogen had been absorbed, the catalyst wasseparated by vacuum filtration, and the filtrate was evaporated. Theresidue was dissolved in a mixture of equal parts of methanol andconcentrated hydrochloric acid, and the solution was refluxed for twohours. Thereafter, the methanol was distilled off, the residue wasallowed to cool, and the precipitate formed thereby was recrystallizedfrom ethanol, yielding u-cyclopentylamino- 2 methoxy3,4-dihydroxy-acetophenone hydrochloride, M.P. 202203 C.

6 gm. of the aminoketone thus obtained were dissolved in methanol, andthe solution was hydrogenated at room temperature and atmosphericpressure in the presence of platinum as a catalyst until the theoreticalamount of hydrogen had been absorbed. Thereafter, the catalyst wasfiltered oil, the filtrate was evaporated, and the residue was heatedwith acetonitrile, whereby the initially oily product becamecrystalline. 1- (2-methoxy-3,4-dihy- 6 droxyphenyl)-2-cyclopentylamino-ethanol-( 1 hydrochloride, M.P. 161-162" C., of theformula HO OCH! CRT-CH9 HO- (|)H-CHr-NHCH HCl OH 0112- Hz was obtained.

EXAMPLE 2 Preparation of 1-(2-methoxy-3,4'-dihydroxy-phenyl)-2-(tert.butyl-arnino)-ethanol-(1) by method A A mixture consisting of gm.of a-bromo-2-methoxy- 3,4-diphenylmethylenedioxy-acetophenone, 500 cc.of benzene and 32 gm. of tert.butylamine was refluxed for two hours.Thereafter, the benzene was distilled oil in vacuo, the residue wastaken up in ether, the insoluble tert.-butylamine hydrobromide wasseparated by vacuum filtration, and the filtrate was evaporated in vacuoafter having been washed with water. The residue was dissolved in ethylacetate, and the solution was acidified with ethereal hydrochloric acid,yieldinga-tert.butylamino-2-methoxy-3,4-diphenylmethylenedioxy-acetophenonehydrochloride, M.P. 182-183 C.

23 gm. of this amino-acetophenone compound were admixed with cc. ofconcentrated hydrochloric acid and cc. of methanol, and the mixture wasboiled for two hours. Thereafter, the methanol was distilled off invacuo, benzene was added to the residue, and the mixture of benzene andwater was distilled off. The residue was stirred with hot methyl ethylketone and ethyl acetate, whereby it crystallized. The crystallineproduct was recrystallized from a mixture of ethanol and ether, yieldinga-tert.butylamino-2-methoxy-3,4-dihydroxy-acetophenone hydrochloride,M.P. l89190 C.

15 gm. of the amino-acetophenone salt thus obtained were dissolved incc. of methanol, and the solution was hydrogenated at standardtemperature and pressure in the presence of platinum as a catalyst untilsubstantially the theoretical amount of hydrogen had been absorbed.Thereafter, the catalyst was removed by vacuum filtration, the filtratewas evaporated, and the residue was recrystallized from acetone,yielding l-(2'-methoxy- 3',4' dihydroxy-phenyl)-2-tert.butylamino-ethanol-(l) hydrochloride with V2 mol of water ofcrystallization, M.P. 97-99" C.

EXAMPLE 3 Preparation of 1-(2'-methoxy-3,4'-dihydroxyphenyl)- 2-1,l-dimethylpropylamino)-ethanol-(1 HO (')CH:

CHa HO- CHOH-CHpNH-(-CHPCHi'HO 0 C-CuHs EXAMPLE 4 Using a procedureanalogous to that described in Example 1,1-(2'-methoxy-3',4'-dihydroxyphenyl-2-[p-(4- 7hydroxyphenyl)-ethylamino]-ethanol-(1 benzoate, M.P. 90 C. of theformula -OH-HO O C-CeHs Using a procedure analogous to that described inExample 1, 1-(2-methoxy-3,4'-dihydroxyphenyl)-2-[fl-(2-methyl-4-hydroxyphenyl) -ethylamino] -ethanol- 1 benzo ate, M.P. 153-155C., of the formula no 00H;

was prepared fromu-[p-(2-methyl-4-hydroxyphenyl)-ethylamino]-2-methoxy-3,4-dihydroxyacetophenonebenzoate (M.P. ZOO-203 C.) which in its turn was obtained from a-[fl (2methyl 4 hydroxyphenyl)ethylamino]-2- methoxy 3,4diphenylmethylenedioxy-acetophenone hydrochloride (M.P. 153-155 C.).

EXAMPLE 6 Using a procedure analogous to that described in Example 1,1-(2'-methoxy-3',4-dihydroxyphenyl)-2-[5-(4-hydroxyphenyl)-a,a-dimethylethylamino] -ethanol- 1 M.P. 122 C., of the formula no OCH:

CH: no -CH-OH-CHzNH-i-CHz-OH was prepared froma-[B-(4-hydroxyphenyl)-a,a-dimethylethylamino]-2-methoxy-3,4-dihydroxyacetophenonehydrochloride (M.P. 251 C.), which in its turn was obtained froma-[fl-(4-acetoxyphenyl)-a,a-dimethylamino]-2-methoxy-3,4-diphenylmethylenedioxy-acetophenone oxalate (M.P. 189 C.)by hydrolysis.

EXAMPLE 7 Using a procedure analogous to that described in Example 1,l-(2'-ethoxy 3'4 dihydroxyphenyl)-2-(tert.- butylamino)-ethanol-(1)hydrochloride, M.P. 159-160 C., of the formula HO O CzHl CHI wasprepared from a-(terL-butylamino)-2-ethoxy-3,4- dihydroxyacetophenonehydrochloride (M.P. 199-203 C.), which in its turn was obtained froma-(terL-butylamino) 2 ethoxy 3,4 diphenylmethylenedioxy-acetophenonehydrochloride (M.P. 168172 C.).

EXAMPLE 8 Using a procedure analogous to that described in Example 1,1-(2'-ethoxy-3,4'-dihydroxyphenyl)-2-cyclopen- 8 tylaminoethanol-(l)hydrochloride, M.P. 17 3-174" C., of the formula HO OCzH5 CH2-CH1 wasprepared from a-cyclopentylamino-2-ethoxy-3,4-dihydroxy-acetophenonehydrochloride (M.P. ZOO-202 C.), which in its turn was obtained fromot-cyclopentylamino-2-ethoxy-3,4 diphenylmethylene dioxy aceto phenonehydrochloride (M.P. -197 C.).

EXAMPLE 9 Using a procedure analogous to that described in Example 1, 1(2' ethoxy-3,4-dihydroxyphenyl)-2-[fit-(2-methyl-4-hydroxyphenyl)-ethylamino]-cthanol (1) benzoate, M.P. 172-174C., of the formula HO OCzHs Q-OH-HO 0c on1,

(3H3 was prepared from a-[fl-(2-methyl-4-hydroxyphenyl)-ethylamino]-2-ethoxy-3,4'dihydroxy acetophenone benzoate (M.P. 166-168C.), which in its turn was obtained from a[}3 (2methyl-4-hydroxyphenyl)-ethylamino]-2-ethoxy-3,4-diphenylmethylenedioxy-acetophenone hydrochloride (M.P.148-150 C.).

EXAMPLE 10 Using a procedure analogous to that described in Example 1,1-(2-methoxy-3',4'-dihydroxyphenyl)-2-[fl-(2- methyl 4 hydroxyphenyl)ethylamino] butanol (l) benzoate, M.P. 158160 C., of the formula HO OCH:

i-CH3 Q-OH-HO 00-min was prepared from a-ethyl-a-[3-(2-methyl-4-hydroxyphenyl) ethylamino] 2methoxy-3,4-dihydroxy-acetophenone benzoate, which in its turn wasobtained from a-ethyl-a-[fl-(2-methyl-4 hydroxyphenyl) ethylamino]-2-methoxy-3,4 diphenylmethylenedioxy acetophenone benzoate.

The compounds according to the present invention, that is, racemicmixtures of those embraced by Formula 1, their pure stereoisomers,diastereomeric antipode pairs thereof, and non-toxic, pharmacologicallyacceptable acid addition salts of any of these, have usefulpharmacodynamic properties. More particularly, they exhibitsympathomimetic activities in warm-blooded animals, such as mice andrats; especially, they exhibit bronchospasmolytic and antipuriticactivities and dilate the peripheral blood vessels in warmbloodedanimals, such as those above referred to.

Particularly active in this respect are those compounds of the Formula Iwherein R is methoxy, R is hydrogen, methyl or ethyl, and R is alkyl of4 up to 8 carbon atoms, cycloalkyl of 5 carbon atoms or a substituent ofthe Formula Ia where Z is alkylene of 2 to 4 carbon atoms.

For pharmaceutical purposes the compounds of the present invention areadministered to warm-blooded animals topically, perorally orparenterally as active ingredients in customary dosage unitcompositions, that is compositions in dosage unit form consistingessentially of an inert pharmaceutical carrier and one elfective dosageunit of the active ingredient, such as sprays, tablets, coated pills,granulates, suppositories, ointments, solutions or suspensions. Oneeffective dosage unit of a compound according to the present inventionis from 0.01 to 10.0 mgm./kg. body weight.

EXAMPLE 11 Tablets The tablets are compounded from the followingingredients:

Compounding procedure The1-(2'-methoxy-3',4-dihydroxy-phenyl)-1-hydroxy-2-tert.-butylamino-ethane hydrochloride is thoroughly admixed with thelactose, 25.0 parts of the corn starch and 4.0 parts of the SiO and theresulting mixture is uniformly moistened with a 5% ethanolic solution ofthe polyvinyl pyrrolidone. The moist mass is then passed through a 1 mm.mesh screen. The resulting granulate is dried for about 24 hours at 60C. in a drying chamber with fresh air circulation. The dry granulate isagain passed through a 1 mm. mesh screen. 70.0 parts of this granulateare admixed in a suitable mixer with a mixture consisting of theremainder of the Si0 the remainder of the corn starch and all of themagnesium stearate, this mixture having previously been passed through a1 mm. mesh screen. The resulting mixture is then pressed into tabletsweighing 80 mgm. each and containing 5.0 mgm. of the active ingredient.These tablets break up in the stomach within fifty seconds.

EXAMPLE 12 2% inhalation solution These ingredients form a clear,colorless solution with a pH of 3, which may be dispensed with the aidof an aerosol inhalation vaporizer, having an aerosol output capacity of12.5 liters per minute for bronchospasmolytic therapy.

EXAMPLE 13 Ampules with hypodermic solution Each ampule contains thefollowing ingredients:

1-(2'-methoxy 3',4' dihydroxy-phenyl) 2 (tert.-

butylamino)-ethanol-(l) hydrochloride mgm.. 0.5

Sodium pyrosulfite --mgm-.. 0.1

Disodium salt of ethylene diamine-tetraacetic acid mom 0.5

Sodium chloride gm 8.0

A N HCl, q.s. ad Ph 3.

Distilled water ml 1.0

10 EXAMPLE 14 Suppositories The suppositories are compounded from thefollowing ingredients:

Parts 1-(2'-methoxy-3,4-dihydroxyphenyl)-2-[fi-(phydroxyphenyl)-ethyl-amino]-ethanol-(1) hydrochloride5.0 Lactose, powdered 45.0 Suppository base (cocoa butter) 1650.0

Total 1700.0

Compounding procedure The 1-(2'-methoxy-3',4-dihydroxy phenyl)-2-[fi-(phydroxy-phenyl)amino] ethanol (l) hydrochloride is thoroughlyblended with the powdered lactose and the resulting mixture ishomogeneously distributed in the molten cocoa butter. The composition isthen poured into suppository molds holding 1.7 gm. of the composition.Each suppository contains 5 mgm. of the active ingredient.

EXAMPLE 15 Starch capsules for peroral administration The contents ofthe capsules are compounded from the following ingredients:

propylamino)-ethanol-(1) hydrochloride is gradually admixed with thelactose. When all of the lactose has been incorporated, the mixture isblended with the corn starch. The resulting mixture is filled intocapsules holding 1 gm. of the mixture. Each capsule contains 5.0 mgm. ofthe active ingredient.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that our invention is not limited to those particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:

1. A racemic mixture of compound of the formula H0 Ili wherein R isstraight or branched alkoxy of 1 to 5 carbon atoms,

R is hydrogen or lower alkyl, and

R is alkyl of 4 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or

where Z is alkylene of 2 to 6 carbon atoms, R; is hydrogen or methyl,and R is hydroxyl or methoxy; a pure stereoisomer thereof; adiastereomeric antipode pair thereof; ora non-toxic, pharmacologicallyacceptable 11 12 acid addition salt of said raeemic mixture,stereoisomer a pure stereoisomer thereof, a diastereorneric antipodedlastel'eomeflc P P P pair thereof; or a non-toxic, pharamacologicallyaccepta- A racemlc mixture of a compound of the formula ble acidaddition salt of said racemic mixture, stereo- HO f 5 isomer ordiastereomeric antipode pair. References Cited OH FOREIGN PATENTSwherein R1 is methoxy or ethoxy, 10 230,352 12/1963 Austria 260570.6 Ris hydrogen, methyl or ethyl, ROBERT INES P E R is alkyl of 4 to 5carbon atoms, cyclopentyl, or H nmary Xammer R10 US. Cl. X.R. Z r260-3405, 343.7, 348 A, 348 R, 348.6, 501.11 501.18.

where Z is alkylene of 2 to 6 carbon atoms, R hydrogen or methyl, and Ris hydroxy;

13%; UNITED STATES PATENT OFFICE I A CERTIFICATE 0F CORRECTION Patent:No. 3,804,83 Dated A ril 16, 19711 ANTON MEN'IRUP, KURT scHRoMM, OTTO'IHOMA, KARL ZEILE Inventofls) It is. certified that error appears inthe above-identified pats-mt and that said Letters Patent are herebytoxrected as shown below:

99 7 line 5 5 y I I 1 Q that portion of the formula which reads"CH--OH--" should reas:

CHOH- Signed and sealed this 19th day of November 197A.

( Attes't:

MCCOY M GIBSONJR. c'. MARSHALL DANN Commissioner of Patents AttestingOfficer

